NL1025900C2 - Use of a proline-enriched composition containing whey proteins to prepare a food or therapeutic composition for correcting, preventing or reducing intestinal wall hyperpermeability - Google Patents

Abstract

Composition comprising a protein fraction containing more than 50 wt.% whey proteins consisting at least in part of alpha -lactalbumin, where the composition is enriched with proline so that the proline:tryptophan ratio is more than 4.2, is used to prepare a food or therapeutic composition for correcting, preventing or reducing intestinal wall hyperpermeability. ACTIVITY : None given. No biological data given. MECHANISM OF ACTION : None given.

Description

Title: Use of proline-enriched compositions for the preparation of foods and therapeutic compositions.

The invention relates to the use of proline-enriched compositions for the preparation of foods and therapeutic compositions, and in particular of infant and diet foods, as well as to therapeutic formulations. These compositions comprise a milk protein fraction that is rich in whey proteins and in particular α-lactalbumin (α-La). In particular, these nutritional compositions and therapeutic formulations include: foods for poorly fed or unhealthy adults, sports foods hypoallergenic and enteral clinical foods, and infant foods.

The infant and diet foods, as well as the therapeutic formulations according to the invention, aim to provide the intestinal wall, and in particular the cells in the intestinal wall, with a desired and preferably optimum supply of polyamines. Polyamines include putrescine, spermidine and spermine. These types of compounds promote, as is known, a good development of the intestinal wall, including a good closure of the so-called "tight junctions".

α-La rich whey protein products are frequently used because of their relatively high tryptophan content. For example, breast milk replacements and in particular such substitutes based on 20 cow's milk proteins are humanized by creating a high bovine-a-La content therein; α-La contains a relatively high tryptophan and cysteine content and a relatively low methionine content, bringing the protein fraction in terms of amino acid composition closer to human milk. Due to the relatively high tryptophan content, α-La falls under the "tryptophan-rich" polypeptides, 26 and this latter term is even used as a synonym for α-La. These 1025900 polypeptides in particular contain a high tryptophan content relative to the neutral amino acids valine, isoleucine, leucine, tyrosine and phenylalanine. This is sometimes referred to as a relatively high ratio of Tryp / LNAA (tryptophan / large neutral aminoaddsN).

Such a high (er) ratio of Tryp / LNAA is associated with an increased serotonin production in the body, in particular in the brain.

Partly because of this, the use of tryptophan-rich polypeptides I products, such as α-La, is linked to improved well-being, improved sleep behavior, a positive influence on the biological clock and improved sleep and wake rhythm, reduced crying in babies and small children, as well as a reduced occurrence of depression, anxiety and fut or listlessness. Furthermore, bulimia and pre-menstrual pains are prevented or at least inhibited.

I In addition, a link has been established with a reduced risk of allergies.

See in this connection, inter alia, German Offenlegungsschrift 4,130,284, EP-A-0 951 842, WO-A-99/55174, WO-A-I 98/14204 and the articles of Heine et al. Acta Paed. 85 (1996) 1024-1028 I and in J. Nutr. 121 (1991) 277-2.83.

I For the human body it has been found that a Tryp / LNAA ratio

I which is greater than 0.05 and advantageously between 0.05 and 0.2 gives advantages. The said ratio also has a regulating influence on the melatonin production.

It is this type of product for which the present invention aims to give a positive effect on the polyamine economy. Incidentally, it is already known that the compounds ornithine and arginine can make a positive contribution. These compounds are precursors and are converted in the body to putrescine, spermidine and spermine. I hereby refer to Applicant's WO-A-01/58283.

The preparation of α-La-rich whey products that can form a component of the compositions according to the invention has been extensively described in the prior art. Reference is made in particular to EP-A-1 1025900-3604 684, EP-A-1133 238, US-A-4,485,040 and WO-2001-06243.

The present inventors have found in metabolic studies that for a favorable or optimal supply of the intestinal wall with polyamines or the precursor ornithine, a good proline and preferably also a good argmin provision are important when starting from whey protein-rich formulations, and in particular of α-La containing or enriched formulations. As far as is known, no significance has ever been attached in the prior art to the fact that when using α-La-like starting products, the content of, in particular, the amino acids proline and arginine is reduced considerably considerably.

Thus, proline has so far been considered a non-essential amino acid. It is therefore not included in the EC directives of 14 May 1991 on infant formulas and follow-on formulas 15 (91/321 / EEC). Arginine is considered a semi-essential amino acid, the necessity of which is only given in catabolic diseases or disorders. As such, this amino acid is included in the directive.

More in detail the invention relates to the use of a composition, and in particular a composition for enteral and in particular oral use, which composition comprises a protein fraction which contains more than 50% by weight of whey proteins, which whey proteins extract or consist in part of α-lactalbumin; and which composition is enriched with proline, such that the ratio of proline: tryptophan is> 4.2, for the preparation of a food or therapeutic composition for the repair, prevention or reduction of undesirable permeability or hyperpermeability of the intestinal wall. The composition comprises in particular proteins at the ratio of casein: whey proteins smaller than 1, preferably 45:55 and more preferably 40:60, which ratio is achieved in particular by the α- Increase La content. These compositions are enriched with proline such that the proline: tryptophan ratio is greater than 4.2 and more preferably greater than 4.5.

In this specification, free and protein bound in protein or oligopeptide 5 are determined or calculated by methods known per se, such as described, for example, by Walstra in Dairy Chem. Phys. (1984) 402-403 or by Bidlingmeyer in J. Chromatography (1984), 93-104. In the event of differences, the Walstra method is decisive.

In a preferred embodiment, the food or therapeutic composition according to the invention is also enriched with arginine, and preferably such that the ratio (proline + arginine): tryptophan is greater than 5.8, and more preferably greater than 6.0.

Furthermore, the foodstuff preferably also contains an additional amount of glutamine and / or glutamate, or glutamine and / or glutamate-containing raw materials or suitable sources of glutamate and / or glutamine (also referred to as "glutamic acid equivalents") are added, such as glutamic acid α-ketoglutarate, glutamate salts, glutamine, glutamate / glutamine di- and tripeptides, glutamate and / or glutamine-containing protein hydrolysates, glutamate-containing probiotics, glutathione.

Without wishing to be bound by any hypothesis, it is indicated that the advantageous properties of the products according to the invention are related to the fact that ornithine, the precursor of the polyamines putrescine, spermidine and spermine, in the body from proline (+ glutamate) and arginine is synthesized. To this end, reference is made to the diagram shown in Figure 1.

1 O95Q00 -5-

Thus, proline, and preferably also arginine, forms a natural "pool" for the synthesis of ornithine, which pool should be filled as well as possible, for example (and preferably) in the stage of intestinal wall maturation after birth, or for the prevention and treatment of excessive or undesired permeability of the intestinal wall, or a good closure of the tight junctions.

Therefore, the invention also provides for the use of the foods and therapeutic agents of the invention in the preparation of therapeutic agents for the purposes described in the preceding paragraph.

In the light of the invention, it should be borne in mind that the polyamines as presented in foods via animal milk ingredients such as whey and desalted whey are hardly significant, 1025900 H when a comparison is made with human breast milk. It is therefore important to achieve an optimum supply of polyamines through the presence of proline and preferably also arginine as components of the precursor source. Thus, according to the invention, proline appears to be semi-essential to humans, such as arginine that was already in the case of catabolic diseases.

Incidentally, it was already known to include the relevant polyamines, such as putrescine, spermine and spermidine, in food products with a milk protein I fraction, as described in WO 01/58283. However, this has a number of disadvantages. First, the cost of such food products is disproportionately increased. Moreover, these substances are not sufficiently available in the quality I required for use in food products. In addition, due to the direct addition of polyamines, the optimal provision on the intestinal wall, for example in the phase of intestinal maturation after birth, is difficult to control. The addition of proline I and proline and arginine to food products with a milk protein fraction rich in α-La compared to the addition of I polyamines themselves therefore has advantages.

For the metabolic synthesis of the polyamines via the proline ornithine precursor, a good provision of glutamine and / or glutamic acid is also important. These latter amino acids are generally widely available in the milk proteins. In certain circumstances, however, it is preferable to add glutamine and / or glutamic acid or peptides rich in glutamine and / or glutamic acid in a readily available form. For example, in the case of oral I to provide nutrients. The percentage of glutamine or glutamic acid to be added separately can be 0.05-1% (based on the dry matter content). As said, various methods are known for obtaining α-La from milk protein or whey protein, see, inter alia, EP 0 604 684, EP 1133 238, US-A 4,485,040, JP 3044487 and WO 01/05243. Older techniques isolate the protein fraction by, among other things, lowering the pH, whereby protein coagulates, or by predpitation. More modern techniques win α-La through ultrafiltration. This latter technique has the advantage that the separated protein fraction can easily be re-used in foods.

For a single application, including baby milk, it may further be advantageous to remove the caserne macropeptide (GMP) from the whey proteins.

The underlying invention preferably relates to a product, for example a child * and diet food or a therapeutic agent, which is enriched with nutrients, such as in particular milk proteins or products derived therefrom, such as whey proteins, skimmed milk, caseins, desalted or not whey and / or whey proteins, whey (proteins) enriched with α-La, lactoferrin and furthermore lactose, galactoligosaccharides, sialyl lactose, sialyloligosaccharides, sialyl-rich milk proteins or sialyl-rich milk protein hydrolysates and partially or extensively hydrolysed milk protein hydrolysed. In particular, the use of the aforementioned milk protein hydrolysates, wherein the proteins are hydrolyzed at least for 20-100%, preferably up to 80 or 70% based on the -NH-CO bonds, leads to products that are highly preferred, because thus products with hypoallergenic properties are obtained or products that promote tolerance to milk protein sensitivity and in particular such hypersensitivity. Such an application leads to preventive tolerance induction and reduction of allergies associated with milk proteins.

The present invention also comprises the preparation of a product which is enriched with nutrients, such as in particular vegetable proteins, for example from soy or wheat, or (glutamine-rich) hydrolysates prepared therefrom.

Children's and dietary foods or therapeutic agents prepared using the present invention sometimes include hydrolyzates advantageously prepared from proteins, such as those obtained using pancreatic enzymes for the purpose of preventing allergies. Such hydrolyeates are relatively richer in polyamines, such as putrescine, spermidine and spermine. Also by-products from the lactofemne / lactoperoxidase preparation can form a source rich in polyamines such as putresdne, spermidine and spermine.

Conventional micro-ingredients are added to the type of product prepared according to the invention, such as vitamins, further amino acids, minerals, taurine, carnitine, nudeotides and polyamines (such as putrescine, spermidine and spermine). In addition, antioxidants such as BHT, aecorbyl palmitate, Vitamin E, α and β-carotene, lutein, zeaxanthin, lycopene and lecithin can be added. In the case of 15 infant formulas, the concentrations and proportions between these active substances are adjusted as much as possible to breast milk or to the special needs of the child.

A preferred embodiment of the invention relates to the use in a childhood or dietary or therapeutic diet of a composition in which in particular the milk proteins are rich in whey proteins, more particularly in which the milk proteins are rich in α-La, in particularly further enriched with the amino acid proline, the amino acids proline and arginine, respectively. Furthermore, fats, most of vegetable origin, are added. In addition, these food products can be enriched with raw materials that specifically provide polyunsaturated fatty acids, such as gamma linolenic acid (GLA), dihomo-gamma linolenic acid (DHGLA), arachidonic acid (AA), stearidonic acid (SA), eicosapentaenoic acid (EPA), docosahexaenoic acid ( DHA) and docosapentaenoic acid (DPA).

1025900-9

With a view to the good development of the intestinal flora, probiotics can be added, such as lactobadlles and / or bifido bacteria, as well as prebiotics. A preferred combination of probiotics involves, for example: Bifidobacterium Bb-12 with L-paracasei or L. Reuter.

Examples of prebiotics include fructo and / or galacto-oligoaccharides, both short and long-chained, sialyloligosaccharides, branched (oligo) saccharides, sialic acid-rich milk products or derivatives thereof, inulin, locust bean gum, gums, whether or not are hydrolysed, fibers, protein hydrolysates, nudeotides etc.

The present invention is now illustrated by the following non-limiting examples.

Example 1

A complete infant formula has been prepared that is specifically suitable for infants born in a term, in which the milk proteins mostly consist of whey proteins, and to which in particular the amino acid proline has been added. It is a composition that contains the following components per 100 grams:

Example 1 gr "**

Protein (casein / whey white = 40/60) __ 10.8

Bold__27

Carbohydrates (lactose) __ 57

Minerals and micro-ingredients__2.35

Proline__0.05

Water__2Λ 20 Total__100

Table 1

The proline / tryptophan ratio in the composition of Example 1 was 5.1 / 1.

The ratio (proline + arginine) / tryptophan in the composition of Example 1/25 was 7.2 / 1.

1025900-I 10 I Example 2.

A complete infant formula was prepared according to Example 1, which is specifically suitable for a term born children, in which 60% of the milk proteins I5 consist of whey proteins, and in which the whey proteins are rich in I a-La (45% α -La). In particular, a supplement with 350 mg of the I amino acid proline is added (added via the minerals and micro I ingredient mix).

The proline / tryptophan ratio in the composition of Example 2 was 6/1.

The ratio (proline + arginine) / tryptophan in the composition of Example 2 I was 6.6 / 1.

I Example 2 gr I Protein (casoine / wet protein = 40/60) 10Λ I Vit 27 I Carbohydrates (lactose) 57

Minerals and microlnedients 2.35 I Proline 0.35 I Water ÜT5 I Total ÏÖÖ I Table 2 I 15 The following table shows that addition of extra proline to the α-I La-enriched formula leads to the desired ratio between proline and tryptophan on the one hand and proline + arginine and tryptophan on the other.

I 1025900-11

Table 8. The amount of amino acid and the mutual ratio gr / 100 gr 5 Free added Proline 0.35

Total proline 1.11

Tryptophan 0.22

Arginine 0.34

Proline / tryptophan in protein 3.5 10 Total proline / tryptophan 5.0

Proline + arginine / tryptophan in protein 5.0

Total proline + arginine / tryptophan 6.6 Example 3

A complete infant formula was prepared according to example 2, which is specifically suitable for a term born children, in which the milk proteins consist for 60% of whey proteins, which whey proteins are rich in a-La (45% a-La) and in in particular a supplement of 350 mg of the 20 amino acid proline and a supplement of 175 mg of arginine takes place, (added via the mineral and micro-ingredient mix).

The proline / tryptophan ratio in the composition of Example 3 was 5/1. The ratio (proline + arginine) / tryptophan in the composition of Example 3 was 7.4 / 1.

Example 4.

A hypoallergenic diet was prepared in which the milk proteins comprise whey protein hydrolyzate, in particular whey protein hydrolyzate prepared by means of pancreatic enzymes, and which was further enriched with the amino acid proline. In this case, (milk) protein is understood to mean the so-called "N fraction x 6.25". This is a composition that contains the following components per 100 I grams: I Example 4 g I Protein (polyamine-rich hydrolyzed) 11.7

Fat__27 I Carbohydrates (iactose) __ 20 I Carbohydrates (glucos estroop) __ 35.5 I Minerals and micro-ingredients 3 I Proline 0.1 I Water__27 I Total 100 I The amount of amino acids and their proportions are shown in the following table: size / 100 g I Freely added proline 0.1 I Total proline 0.85 I Tryptophan 0.19 I Arginine 0.49 I Proline / tryptophan in whey protein hydrolyzate N 3.9 I Total proline / tryptophan 4.5 I Proline + arginine / tryptophan in whey protein hydrolyzate 6.5

IN

Total proline + arginine / tryptophan 7

The proline / tryptophan ratio in the composition of Example 4 was 4.5 / 1.

The ratio (proline + arginine) / tryptophan in the composition of Example 4 was 7.1 / 1.

5

Example 5

A problem-solving diet was prepared, in particular of optimal digestion and utilization to prevent digestive disorders, in which the milk proteins are enriched with whey proteins, more particularly in which the whey proteins are rich in a-La (60% α- La), and further enriched with the amino acid prouse, respectively the amino acids proline and arginine, oligosaocharides, glutamic acid and a mineral and micro-ingredient mix. This is a composition that contains the following components per 100 grams: {Example 5 Igr

Protein (caselne / Welelwit = 45/55) __ 22

Vel_ 18.5

Carbohydrates (lactose) 38

Carbohydrates (sucrose) 10

Fructo-oligosaccharlden (short throats <6) 2

Fructo-olioosaocharides (long chain> 6) 2

Minerals, vitamins, probtoBca, nudeotides__4.65

Glutamic acid 0.1

Proline 0.25

Water 2.5 15 iTotal 100 / 1025900-

The amount of amino acid and the mutual ratio appear from the following table: I gr / 100 gr I 5 Freely added Proline 0.25 I Total proline 1.86 I Tryptophan 0.44

Arginine 0.7 I Proline / tryptophan in protein 3.7 I 10 Total proline / tryptophan 4.2 I Proline + arginine / tryptophan in protein 5.3

Total proline + arginine / tryptophan 6.8 I The ratio proline / tryptophan in the composition of Example 5 was I 4.2 / 1.

The ratio (proline + arginine) / tryptophan in the composition of Example 5 I was 5.8 / 1.

Example 6.

A problem-solving diet was prepared according to Example 5, with the addition of 0.2 grams of arginine.

The proline / tryptophan ratio in the composition of Example 6 was I 4.2 / 1.

The ratio (proline + arginine) / tryptophan in the composition of Example 6 I was 6.3 / 1.

H

I 1025900

Claims (7)

Use of a composition comprising a protein fraction with more than 50% by weight of whey proteins, which whey proteins consist wholly or partly of α-lactalbumin; and which composition is enriched with proline, such that the ratio of prolinettryptophan is> 4.2, for the preparation of a food or therapeutic composition for the repair, prevention or reduction of undesirable permeability or hyperpermeability of the intestinal wall. The use according to claim 1, wherein the food or therapeutic composition is also enriched with arginine such that the ratio (proline + arginine): tryptophan is> 5.8. Use according to claim 1 or 2, wherein the milk protein is partially or extensively hydrolysed. Use according to any one of the preceding claims, wherein the food or the therapeutic composition further comprises freely added glutamine and / or glutamic acid, or peptides rich in glutamine and / or glutamic acid. 5. Use according to any one of the preceding claims, wherein the food or therapeutic composition further comprises one or more antioxidants selected from the group consisting of BHT, ascorbyl palmitate, vitamin E, α and β-carotene, lutein, zeaxanthin, lycopene and lecithin . Use according to any one of the preceding claims as baby food or infant food. The use according to claim 6, wherein the food is hypoallergenic or promotes tolerance to milk protein in babies or children who are sensitive to milk protein. 1025900